title: ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer.
abstract: We report the spectrum of 59 ATM mutations observed in ataxia-telangiectasia (A-T) patients in the British Isles. Of 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. We report, in two A-T families, an ATM mutation (7271T-->G) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes (relative risk 12.7; P=. 0025), although there is a less severe A-T phenotype in terms of the degree of cerebellar degeneration. This mutation (7271T-->G) also allows expression of full-length ATM protein at a level comparable with that in unaffected individuals. In addition, we have studied 18 A-T patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in these patients. We also show that 25% of all A-T patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein.
authors.affiliation: CRC Institute for Cancer Studies, The Medical School, University of Birmingham, United Kingdom.
authors.forename: T
authors.initials: T
authors.lastname: Stankovic
authors.forename: A M
authors.initials: AM
authors.lastname: Kidd
authors.forename: A
authors.initials: A
authors.lastname: Sutcliffe
authors.forename: G M
authors.initials: GM
authors.lastname: McGuire
authors.forename: P
authors.initials: P
authors.lastname: Robinson
authors.forename: P
authors.initials: P
authors.lastname: Weber
authors.forename: T
authors.initials: T
authors.lastname: Bedenham
authors.forename: A R
authors.initials: AR
authors.lastname: Bradwell
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
authors.forename: G G
authors.initials: GG
authors.lastname: Lennox
authors.forename: N
authors.initials: N
authors.lastname: Haites
authors.forename: P J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: A M
authors.initials: AM
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins; D005260:Female; D006580:Genetic Carrier Screening; D005819:Genetic Markers; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D016350:Leucine Zippers; D007938:Leukemia / Q000453:epidemiology / Q000235:genetics*; D008223:Lymphoma / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins; D006113:United Kingdom
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases